ANCA -Associated Vasculitis Maryam Miri Assistant Professor of - PowerPoint PPT Presentation

ANCA -Associated Vasculitis Maryam Miri Assistant Professor of Nephrology At MUMS

Melborne 1982:First description of ANCA D J DAVIES,1982

Distribution of vessel involvement in vasculitis

Epidemiology • Annual incidence of AAVs : 13 to~20 cases per million individuals. • Prevalence : 46 to~184 cases per million individuals worldwide. • EGPA is less common than GPA or MPA EGPA annual incidence : 0.5-2.0/million , prevalence of 10-45/ million • The gender distribution is fairly similar . • Peak incidence occurs in the middle of the sixth decade of life .

Genetic Associations in ANCA Associated Vasculitis • In anti-PR3 AAV was associated with : • HLA-DP: HLA-DRB1*15, HLA DPB1*0401 • PRTN3 (the gene encoding proteinase-3) • SERPINA1 (the gene encoding a1-antitrypsin, a circulating inhibitor of PR3) • In anti-MPO AAV was associated with: • HLA-DQ

Environmental Associations and Im Immunogenicity of f ANCA • Silica • Bacterial species Staphylococcus ,Streptococcus • Virus species Parvovirus B-19 ,Epstein-Barr virus ,Ross River Virus • Antibiotics: Cefotaxime ,Minocycline • Antithyroid drugs : Methimazole ,Propylthiouracil • Anti-tumor necrosis factor agents : Adalimumab,Etanercept ,Infliximab • Psychoactive agents: Clozapine ,Thioridazine • Miscellaneous drugs : Allopurinol ,D-Penicillamine,Hydralazine,Levamisole

His istorical la landmarks of f ANCA-testing in in small vessel vasculitis : Bossuyt,NATURE REVIEWS RHEUMATOLOGY2017

Comparison of f the specificity and sensitivity for different ANCA assays Bossuyt,NATURE REVIEWS RHEUMATOLOGY2017

Vis isual representation of the 1999 recommendations and revis ised 2017 recommendations. . Bossuyt,NATURE REVIEWS RHEUMATOLOGY 2017

Clinical indications for ANCA testing Bossuyt,NATURE REVIEWS RHEUMATOLOGY 2017

PATHOGENESIS

Study of autoantibody epitope specificity Location of epitopes on the MPO molecule. within an MPO-ANCA – positive cohort

Cells and Pathways In Involved in in AAV Pathogenesis and Regulation of f the Im Immune Response • Neutrophils in AAV • Lymphocytes in AAV • Complement in AAV

Neutrophil depleted anti Anti MPO IgG MPOIgG REcipients recipients Crescent 11% Crescent 0% Segmental nec 6% Segmental nec 0% XxxxXiao H et al ,Amj 2005

Lymphocytes in AAV

Crescent 30% to 3% J Am Soc Nephrol 2014

The ACR/EULAR 2017 Provisional Classification Criteria for GPA

Classification schema for ANCA-associated GN

TREATMENTS

Remission and relapse in MYCYC Study

115 patients 58 (AZA) 57(RTX) 28mo F/u

MAINRITSAN2 • rituximab at randomization: • 1.ANCA and CD19+ B lymphocytes were assessed every 3 mo. 2.The control group received the MAINRITSAN trial. Charles P, et al. Ann Rheum Dis 2018

Features of the compared guidelines • BSR/BHPR 2014 • EULAR/ERA-EDTA 2015 • CANVAS 2016 • SBR 2017 D Geetha et al.KI report 2018

SEVER DISEASE

CYC Difference Common view • SBR and CanVasc : Either oral or i.v . • CYC pulsed CYC. • with high-dose steroids for first-line • BSR and EULAR : Favor i.v. pulsed CYC induction is universally recommended • Dosing BSR, SBR: Standard 15 mg/kg, • GC ‏ &CYC therapy should be max 1.2 g (SBR) continued for 3-6 mo . • 1.5 g (BSR) per pulse, first 3 pulses at • switched to a less toxic maintenance 2-wk intervals, then every 3 wks for therapy when remission is achieved. total of 3-6 mos • Dosing adjustments should be • EULAR : not specified, but refers to • made for age and renal function (BSR, CYCLOPS trial, which is same as the CanVasc, SBR) preceding.

RTX Difference Common view • First line RTX: • BSR and EULAR : recommend RTX first-line in general for all AAV patients. • All 4 guidelines recommend RTX • EULAR notes that the data are with high-dose steroids for first- weakest among patients with EGPA. line induction in patients in • Dosing: whom CYC is contraindicated or • SBR: rituximab should be given at not preferred. 375 mg/m2 weekly for 4 wks , or in 2 infusions 2 wks apart at a dose of 1 g . • BSR and CanVasc : recommend 375 mg/m2 weekly for 4 wks

GC dosing Difference Common view • Oral GC dosing and schedule : • Every patient should receive • BSR : start oral prednisolone at 1.0 mg/kg per day (max, 60 mg/d), tapered to 15 mg per day at 12 wks. systemic GCs. • SBR : start prednisone at 0.5-1.0 mg/kg per day (max, 80 • In severe disease, patient may mg/d) for 14 wks, taper by 10 mg for 24 wks until 20 mg/d, then reduce by 2.55.0 mg every 2 -4 wks until full be started first on i.v. pulse withdrawal. • CanVasc : start prednisone equivalent at 1.0 mg/kg per methylprednisolone. day (max, 60-80 mg/d) for 1 mo, then gradually tapered • EULAR : 1.0 mg/kg per day (max, 80 mg/d) • i.v. pulse methylprednisolone dosing : • BSR : 200-500 mg/d before or with first 2 doses of CYC • CanVasc : 500-1000 mg/d for 1-3 days • SBR : 500-1000 mg/d or 15 mg/kg per day for 1-3 days • EULAR : not specified

IV IVig • SBR : infection and persistent disease • disease refractory to GC ‏ ,CYC , or • contraindications to CYC or RTX • CanVasc : • refractory disease , • pregnant women in whom other immunosuppressants are contraindicated • and those with current severe infection or • recurrent severe infections • EULAR : refractory setting

Others agents Difference Common view • BSR, CanVasc : Possible • Etanercept should not be used experimental options for to treat AAV . refractory disease include • other TNF-a inhibitors have mepolizumab for patients with limited evidence (BSR, CanVasc, EGPA , alemtuzumab (anti- SBR) CD52). • BSR : other experimental options include gusperimus and leflunomide .

Refractory ry Disease • Patients who received CYC : • BSR and EULAR : all refractory patients with severe disease who have failed CYC should receive RTX. • CanVasc : Severe GPA/MPA patients in whom CYC failed should receive RTX. • Patients who received RTX: • EULAR: refractory patients who received RTX should now receive CYC. • Other strategies include adjunct i.v. Ig and • switching from pulsed to oral CYC (when RTX is unavailable/cannot be administered). (EULAR ).

Recommendations for use of plasma exchange in induction therapy ofAAV • 1.RPGN: • CanVasc: adjuvant if a patient is refractory to high dose GC + CYC/RTX. • BSR, SBR, and EULAR recommend consideration of plasma exchange for RPGN with serum Cr greater than w500 mmol/l (5.7 mg/dl). • 2.Diffuse alveolar hemorrhage : • adjuvant when patients are in this setting and refractory to standard GC CYC/RTX (all 4 guidelines) Kidney International Reports (2018)

Maintenance • Agent: • BSR : AZA or MTX with GC. LEF or MMF may be alternatives . RTX is also an option. • CanVasc : AZA or MTX , initially in combination with low-dose GC. LEF and MMF are secondline alternatives. RTX is also an option particularly in PR3- ANCA-positive GPA. • EULAR : Patients with GPA/MPA should receive low-dose GC and AZA, RTX, MTX, or MMF • those with EGPA should receive AZA . • LEF is a second-line option. • TMP/ SMX can be considered as adjuvant therapy.

Maintenance Duration • Duration of immunosuppressant agent in general: • BSR, EULAR: 24 mos after duration . • CanVasc: 18 mos, but no clear evidence. • Duration of immunosuppressant agent for PR3-ANCA ‏ patients: • BSR: up to 5 yrs • EULAR: evidence still pending, but 36 mos • Duration of GCs : • BSR: patients in remission after 1 yr can begin to taper GCs. After GCs are withdrawn, the other immunosuppressive agent can be tapered after 6 mos. • - CanVasc: no clear evidence for GC duration

Relaps Difference Common view • Severe relapse • severe relapse : GC ‏ CYC or RTX • BSR: Severe relapse should be treated with GC ‏ CYC or RTX . If the patient is (BSR, CanVasc, EULAR). trying a second round of GC , ‏ CYC, the • Non severe relapse : dose of GC should be increased; addition of i.v. methylprednisolone • may be managed with increasing and PLEX can be considered. • CanVasc : Patients who already tried the dosage of GC in addition to GC ‏ CYC should receive RTX. optimizing current • EULAR : In general, due to the immunosuppressant agent cumulative toxicity of CYC, RTX is recommended over CYC in relapsing • (BSR, CanVasc, EULAR). disease

Prophylaxis Against Pneumocystis jirovecci • All 4 guidelines recommend prophylaxis for Pneumocysti jirovecci in AAV patients receiving induction therapy with CYC or RTX. • The recommended first-line prophylaxis by all guidelines in the absence of allergy is TMP/SMX at a dose of 400/80 mg daily or 800/160 mg 3 times a week.

Frequency of Disease Assessment • BSR/BHP R recommends: • monthly during remission induction , every 3 months during initial remission maintenanc e treatment, thereafter every 6 months , and then annually • CanVasc: is monthly during remission induction and every 3 months for 2 years while on remission maintenance therapy, and annually thereafter.

EULAR 2017